We reported the identification of highly conserved, homologous regions located in the carboxy-terminus of HIV-1 gp41 (a.a. 837-844), and the N- terminal of human HLA class II beta chains (DR,DQ, a.a. 19-25). This "molecular mimicry" led to the generation of anti-gp41 antibodies which crossreact on "native" class II molecules (CRab). The class II binding activity was demonstrated using : (a) Murine anti-gp41-peptide monoclonal antibodies (mAb). (b) Human mAb 4E10 derived from asymptomatic HIV-1 infected patient. (c) 30-40 % of HIV-1 infected individuals in either early stages (WR 1-3) or late stages of AIDS (WR 4-6). In biological assays it was found that the CRab could block normal immune responses to recall antigens such as tetanus toxoid and flu. These antibodies could also mediate antibody dependent cellular cytotoxicity of HLA class II-positive cells (e.g. B cells, macrophages, activated T cells). In asymptomatic patients (CD4 numbers > 500/ml), production of CRab correlated (p<0.001) with early loss of T cell responses to recall antigens as measured by proliferative responses and IL2 production in vitro. In a cohort of HIV-1 infected hemophiliacs, high titers of CRab was found to correlate with rapid progression (2-4 yrs) to full blown AIDS. We are currently continuing to monitor in parallel : (a) HLA typing, (b) Disease progression, and (c) CRab production, in a cohort of patients from whom multiple sera samples and clinical data are available. We also test sera from various vaccine groups who were immunized with subunit vaccines containing the gp41/HLA class II homologous region, for the presence of CRab.